Mir-494-3p enhances an aggressive phenotype of non-small cell lung cancer cells by regulating SET/I2PP2A
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ABSTRACT:
PROVIDER: PRJNA1231405 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32568369_1.fastq.gz | Fastqsanger.gz | |||
| SRR32568369_2.fastq.gz | Fastqsanger.gz | |||
| SRR32568370_1.fastq.gz | Fastqsanger.gz | |||
| SRR32568370_2.fastq.gz | Fastqsanger.gz |
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Project description:High expression of miR-494-3p have been associated with poor prognosis in non-small cell lung cancer (NSCLC). However, the role of miR-494-3p in the development and progression of NSCLC remains elusive. In this study, we found that miR-494-3p was overexpressed in both lung adenocarcinoma and lung squamous cell carcinoma in the Clinical Proteomic Tumor Analysis Consortium and Cancer Genome Atlas databases. A bioinformatic analysis revealed that representative pathways associated with cancer metastasis were enriched in the genes positively correlated with miR-494-3p expression levels, suggesting the potential involvement of miR-494-3p in aggressive properties of NSCLC. To identify potential targets of miR-494-3p, we explored genes inversely correlated with miR-494-3p in the mRNA expression datasets of NSCLC cell lines obtained from the Cancer Dependency Map. Integration of RNA sequencing analysis of NSCLC cells with miR-494-3p inhibition and a bioinformatic search of miRNA target prediction algorithms resulted in identification of SET/I2PP2A as a direct target of miR-494-3p. We found that suppression of SET/I2PP2A by miR-494-3p promoted cell migration and invasion, but not cell viability, in NSCLC cells, indicative of miR-494-3p and its downstream molecules as potential therapeutic targets in NSCLC with aggressive phenotypes.
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Project description:As recently reported by our group, we performed miRNA and gene expression profiling of CD34+ hematopoietic stem/progenitor cells (HSPCs) isolated from 42 PMF patient samples compared with 31 healthy controls. Integrative analysis of these profiles by means of Ingenuity Pathway Analysis (IPA) allowed the identification of several aberrantly regulated miRNA-mRNA target pairs organized in interaction networks. In particular, our results highlighted the up-regulation of miR-494-3p in CD34+ cells from PMF patients (Norfo R et al, Blood, 2014). Interestingly, among the most upregulated miRNAs, miR-494-3p emerges as being associated to the highest number of downregulated target mRNAs. In order to understand the biological role of miR-494-3p during the hematopoietic commitment and differentiation, we overexpressed this miRNA in cord blood (CB) derived-CD34+ cells. Cells were electroporated with either miR-494-3p miRNA mimic (mimic miR-494) or a negative control mimic (mimic Neg CTR). qRT-PCR confirmed miR-494-3p overexpression 24h and 4 days after transfection (RQ ± SEM, 512.60 ± 137.37, p<.01, and 20.63 ± 3.03, p<.01, respectively). Immunophenotypic analysis of CD41 and CD42b megakaryocyte (MK) lineage differentiation markers, performed on serum-free megakaryocytic ultilineage culture at day 3, 5, 8, 10 and 12, demonstrated that miR-494-3p overexpression induces a significant increase in the MK fraction compared to control samples. Accordingly, morphological analysis of May-Grünwald-Giemsa stained cytospins revealed an expansion of megakaryocytic lineage in samples overexpressing miR-494-3p. These data were further confirmed by collagen-based clonogenic assays which showed a significant increase in the percentage of megakaryocytic colonies in miR-494-3p overexpressing samples compared with controls. In order to better characterize the molecular mechanisms underlying the effects of miR-494-3p on HSPCs differentiation, we performed gene expression analysis of miR-494-3p overexpressing cells 24 hours after the last nucleofection.
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Project description:The microenvironment of injured mucosa has important effects on intestinal stem cell self-renewal and reconstruction of epithelial barrier function in inflammatory bowel disease (IBD). However, the precise status of the interactions between intestinal epithelial cell (IEC) injury, particularly intestinal crypt absence, and microenvironment in IBD is not completely understood. We identified miR-494-3p as important for protection of colonic stemness in intestinal inflammation colonic organoid culture. A novel cytokine-cytokine receptor, EDA-A2/EDA2R, could suppress colonic stemness and epithelial repair during IBD. During intestinal inflammation, high level of LP macrophage-derived EDA-A2 inhibited the nuclear β-catenin/c-Myc axis and organoid growth by targeting EDA2R in colonic crypt stem cells. We further demonstrated that the pro-inflammatory cytokines IL-1β and IL-6 are capable of stimulating macrophages to release EDA-A2 during colitis. Secondly, we identified the cross-talk among IECs, colonic crypts, and lamina propria (LP) macrophages in miR-494-3p-mediated colitis. Furthermore, our study showed that miR-494-3p deficiency in IECs promoted LP macrophage recruitment and M1 activation in DSS-induced colitis mice. In addition, we identified miR-494-3p as critical to dampening IEC injury; specifically, miR-494-3p inhibited inflammation-induced IKKβ/NF-κB activation by targeting the IKKβ 3’UTR in IECs. As such, administration of adequate amounts of a miR-494-3p agomire attenuate colitis in vivo. Consistent with this inference, we showed that miR-494-3p levels were decreased in colonic crypts and serum in colitis mice, and loss of miR-494 potentiated the severity of colonic colitis. Our clinical data on the interactions between miR-494-3p levels in serum exosomes & colonic tissues and associated outcomes support the clinical relevance of miR-494-3p in IBD. The miR-494-3p agomir system, which we designed permits local delivery in vivo in this study, significantly ameliorated the severity of colonic colitis. Our findings no only uncover a miR-494-3p-mediated cross-talk mechanism by which inflamed colonic LP macrophages integrate signals from IECs to regulate colonic stemness and colonic epithelial repair/homeostasis. The miR-494-3p agomir may serve as a potential therapeutic approach in IBD.
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Project description:Accelerated senescence in lung epithelial cells is known to play a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the exact mechanisms underlying the IPF-related epithelial cell phenotype have yet to be elucidated. Increasing evidence supports the concept that extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication that contributes to diverse aspects of physiology and pathogenesis. Here, we demonstrate that lung fibroblasts (LFs) from IPF patients accelerate epithelial cell senescence via EV-mediated transfer of LF-derived pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increase mitochondrial reactive oxygen species (mtROS) and associated mitochondrial damage in lung epithelial cells, leading to mtROS-mediated activation of the DNA damage response and subsequent epithelial cell senescence. We show that IPF LF-derived EVs contain elevated levels of miR-23b-3p and miR-494-3p that are responsible for suppressing SIRT3, resulting in the EV-induced phenotypic changes of lung epithelial cells. Furthermore, we observe that miR-23b-3p and miR-494-3p expression increases in lung epithelial cells from IPF patients’ lungs. Finally, the levels of miR-23b-3p and 494-3p found in IPF LF-derived EVs correlate positively with IPF disease severity. These findings reveal that the accelerated epithelial cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel mechanism in which SIRT3 is suppressed by miR-containing EVs derived from IPF fibroblasts.
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